ABSTRACT Our long-term goal is to elucidate the complex biobehavioral mechanisms responsible for symptoms and healing outcomes for older adults? with venous leg ulcers (VLUs) for the development of targeted therapies that address both the patient-oriented outcomes and healing outcomes in this growing group of affected individuals. VLUs, which account for 70?90% of ulcers found in the lower leg, affect 2 million persons annually, including nearly 4% of people over age 65 years. To date, the basic biology underlying the development and persistence of VLUs and the influence of aging and multiple disease conditions on wound healing are generally not well understood. Individuals living with chronic VLU (CVLU) have a high symptom burden of both wound-related symptoms and symptoms of pain, depression, anxiety, fatigue and cognitive dysfunction, collectively labeled as ?psychoneurologic symptoms (PNS).? Guided by the National Institutes of Health Symptom Science Model (NIH-SSM) framework, the central hypothesis of this application is that there are interrelated molecular mechanisms by which the immune activation that contributes to the development and persistence of CVLU also leads to the development, persistence and severity of PNS. The specific aims of the proposed study are to: (1) Characterize the strength of the associations at baseline among patient-host factors, systemic inflammation, and wound microenvironment with wound area and symptoms (PNS and wound-related); and, (2) Test associations and models over time for: (a) Patient-host factors and systemic inflammation with wound microenvironment; (b) Patient-host factors and wound microenvironment with systemic inflammation; (c) Patient-host factors, systemic inflammation, and wound microenvironment with wound healing; (d) Patient-host factors, systemic inflammation, and wound microenvironment with symptoms (PNS and wound-related) and (e) Patient-host factors, systemic inflammation, wound microenvironment and wound healing with symptoms (PNS and wound-related). To achieve the specific aims, we will longitudinally examine 200 older adults (age >60) who are receiving state of the art, standardized wound treatment biweekly across eight weeks time. We will fully characterize patient-host characteristics (age, comorbidities, sex, race/ethnicity, BMI, nutritional status, lifestyle habits, and wound treatment [pressure therapy, debridement, antibiotics]); systemic inflammatory activation (C-reactive protein and cytokines); wound microenvironment factors (local inflammation [Matrix metalloproteinase (MMP) enzymes C-reactive protein, cytokines], biofilm, and micro RNAs); symptoms (PNS [cognitive dysfunction, pain, fatigue, and depressive/anxiety symptoms] and wound-related); and wound characteristics and healing trajectory at the five timepoints. This knowledge is critical to provide a foundation for developing targeted interventions to address this critical health problem from a holistic perspective and to provide a basis for preventing or reversing the adverse health outcomes of CVLUs, a condition that differentially affects older and minority individuals.